Amino derivatives of tetrasubstituted benzene compounds

ABSTRACT

Antimicrobial 1, 2, 4, 5-tetrasubstituted benzenes having the structure:   WHEREIN R and R&#39;&#39; and may be methyl, or a halogen when R&#39;&#39;&#39;&#39;&#39;&#39; is CH2-; or R and R&#39;&#39;, taken together, may be methylene dioxy; R&#39;&#39;&#39;&#39; may be methyl or nitro; R&#39;&#39;&#39;&#39;&#39;&#39; may be absent or may be -CH2 - or CH ; and X is the residue of a substituted amino or a polyamino radical.

' United States Patent 191 Merianos et al;

[ AMINO DERIVATIVES 0F TETRASUBSTITUTED BENZENE COMPOUNDS 1 [52] US. Cl 424/330, 71/67, 260/340.5,

260/566 F, 260/5705 P, 260/573, 424/282 [51] Int. Cl. A0ln 9/24, AOln 9/20 [58] Field of Search 71/67; 424/330 [5 6] I 1 References Cited UNITED STATES PATENTS 3,645,715 2/1972 Daum et al. 71/67 'June 28, 1974 3,689,504 9/1972 Horrom 424/330 3,697,589 10/1972 Menasse et a]. 424/330 Primary Examiner-James 0 Thomas, Jr. Attorney, Agent, or Firm-Arthur Jacobs, Esquire 57 ABSTRACT Antimicrobial l, 2, 4, S-tetrasubstiituted benzenes hav- I ing the structure:

R RII/X I wherein Rand R and may be methyl, or a, halogen when R" is -Cl-l or Rand R,.taken together, may 3 be methylene dioxy; R may be methyl or nitro;"R"" may be absent or may be CH ir CH=; X is the residue of a substituted'amino or a polyamino radical.

1 Claim, No Drawings R RIIIX wherein R and R may be methyl, or a halogen when R is -CH -;or R and R, taken together, may be methylene dioxy; R may be methyl or nitro; R' may be absent or may be -CH or -CH=; and X is the residueof a lower alkyl, monoor polyamino, or alkanolamino radical.

The configuration of these tetrasubstituted benzenes is mainly, but not necessarily exclusively, 1,2,4,5. For example, the chloromethylation of pseudocumene to trimethylbenzyl chloride by methods known tothe art produces about 80 to 85%of the 2,4,5,-trimethylbenzyl chloride isomer; about -15% of the 2,3,5 isomer; and small amounts of the 2,3,6 isomer. The chloromethylation of 1,2,4-trichlorobenzene yields a similar distribution.

Halogenation of pseudocumene also results in comparable isomeric distribution; of which, for example, the S-halo trimethylbenzene is a solid, which is easily separated from its liquid isomers. The antimicrobial amino derivatives of the present invention will be referred to'hereinafter as the principal l,2,4,5-components, with the understanding that minor amounts of the isomeric compounds may be present.

Among the intermediate agents with which the amino compounds described hereinafter are reacted to produce the products of the invention are trimethylbenzyl halides, trihalobenzyl halides, trimethylhalobenzenes, ti'imethyl benzaldehydes, and nitropiperonal; the halogen in each case being selected from the group consisting of chlorine. bromine and iodine.

The amino compounds which are employed in condensation reactions to yield the products of the invention are organic amines, polyamines, or alkanolamines h'avingat least one primary amino group, such, for example, as ethanolamine, ethylene diamine, propylene diamine, hydroxyethyl ethylene diamine, dimethylaminopropylamine, and the like.

The antimicrobial properties of these products or of I their salts make them effective preservatives, sanitizing and disinfecting agents which are effective against bacteria, fungi and algae. They may be applied to the preservation of cosmetics and to the preservation of waterbased paints, both in the emulsion and in the applied and dried film. They may also be used in the preservation of metal working fluids such as cutting and grinding oils, to prevent putrefaction. They are, additionally, effective for the treatment of process and cooling Water in such fields as paper making and the like, and in heat exchangers, air conditioners, humidifiers and dehumidifiers and the like. They are useful for the sanitization of surfaces and, in fact, whereever an antibacterial agent may be required.

The following examples are intended to illustrate but not to limit the invention, except as claimed:

EXAMPLE 1 Pseudocumene was chloromethylated by the procedure described by R. D. Lake and B. B. Corson, in the Journal of Organic Chemistry, Volume 24, pp. 1823-24. The washed crude was distilled to separate the unreacted residue of hydrocarbon and the small residue of bis-chloromethylated material. The 2,4,5- trimethylbenzyl chloride was obtainedin about 80% yield.

EXAMPLE 2 An agitated, round-bottomed flask fitted with a dropping funnel and a reflux condenser was charged with 150 grams or 2.5 mols of ethylene diamine, and the funnel was'charged with'84 grams or 0.5 mol of the distilled chloromethyl trimethylbenzene of Example 1; this was added slowly, during about /2 hour, to the amine at a temperature of about 120 C, or about the reflux temperature at atmospheric pressure. The cooled mass was checked for ionic chlorine content, which was found to be of the theoretical amount.

100 ml. of caustic soda solution was added with agitation, to liberate the product from its hydrochloride salt. 500 m1. of chloroform was added, and the contents of the flask were transferred to a separating funnel.

The chloroform layer was tapped. off, and transferred to a distilling flask wherein the chloroform was stripped off and recovered.

Distillation was continued, andthe product, trimethylbenzylaminoethylamine, was recovered in 95% of the theoretical amount, distilling at l.22-l25. C at 0.1 mm. pressure. It had an equivalent weight by titration, of 98.7, the theoretical being 96.. The still bottoms represented about 5% of the amount of active product.

The hydrochloride salt was have a melting point of l72l 74 C.

For commercial purposes, it is not necessary to distill the product, but merely to strip off the chloroform.

EXAMPLE 3 In the same manner as in Example 2, the reaction was carried out with, respectively, propylene diamine, 1,3- diaminopropane, dimethylaminopropylamine, hydroxyethyl ethylene diamine, diethylene triamine and ethanolamine,'instead of ethylene diamine.

For example, with dimethylaminopropylamine the reflux temperature was l30l40 C, with diethylene traiamine l50 C, etc.

In each case, the temperature range of about l20-150 C is adequate for a reaction time of about one half hour.

In the case of the high-boiling amines, such as ethanolamine, hydroxyethyl ethylene diamine and the like, it is not necessary to strip off the excess by distillation under high vacuum. Instead, after the addition of caustie and water, the aqueous layer containing the excess amine can be separated from the oily layer, and, thereafter, the water can be largely stripped off from the amine to be recovered by distillation.

EXAMPLE 4 prepared, and found to EXAMPLE 5 An agitated, round-bottomed flask fitted with a reflux condenser was charged with 20 grams or 0.1 mol of the 5-bromopseudocumene of Example 4 and 30 grams or 0.5 mol of ethylenediamine, plus 0.5 grams of cuprous chloride. This was heated under reflux and agitation at about 120 C and atmospheric pressure for 24 hours. When bromide in titration indicated substantially complete reaction, the excess amine was stripped off, and the cooled residue was treated with 30% aqueous caustic soda. The product, trimethylanilinoethylamine was extracted with chloroform and washed with salt solution. The extract was filtered and stripped, of chloroform, and the product was recovered as a solid melting at 22l225 C. The yield was 85-90% of the theoretical.

Similarly, ethanolamine substituted for ethylene diamine and reacted at 170-l75 C for 72 hours yielded trimethylanilinoethanol; and the amines of Example 3 in general may also be reacted.

EXAMPLE 6 l,2,4-trichlorobenzene was chloromethylated by methods known to the art; for example, by treatment with paraformaldehyde and HCl gas in 1 00% sulfuric acid; or with paraformaldehyde and chlorosulfonic acid in concentrated sulfuric acid. The separated and washed product was distilled in vacuo to separate from unreacted trichlorobenzene, to recover the 2,4,5-trichlorobenzylchloride in good yield.

EXAMPLE 7 i 23 grams or 0.1 mol of 2,4,5-trichlorobenzyl chloride and 30 grams or 0.5 mol of ethylene diamine were mixed and heated on a steam bath for 4 to 6 hours until titration of chloride ion indicated essential completion of the reaction. The excess of ethylene diamine was stripped off and the residue was treated with 30% caustic soda and extracted with chloroform.

After distilling off the chloroform, the 2,4,5- trichlorobenzylaminoethylamine was distilled.

In a similar manner, 2,4,5-trichlorobenzyl chloride was reacted with the amines of Example 3, to yield the corresponding trichlorobenzylamino derivatives.

EXAMPLE .8

Schiff bases were prepared by reacting the amines of Examples 1 and 3 with aromatic aldehydes.

The Sommelet reaction (described by Shacklett and Smith, among others, in the Journal of theAmerican Chemical Society, Volume 75, pages 2,65457) was used reacting the trimethyl benzyl chloride of Example 1 with a 10% excess of hexamethylene tetramine and with formalin, in aqueous ethanol. Yields of about 60% of trimethylbenzaldehyde were obtained, in accordance with Shackletts experience.

Thirty grams or 0.2 mol of the trimethylbenzaldehyde and 23 grams or 0.225 mol of dimethylaminopropylamine in 100 ml. of benzene were heated at the reflux temperature, about 80 C, in an agitated flask fitted with a Dean and Stark moisture trap and reflux condenser for about 2 hours. The theoretical amount of water distilled out.

The benzene and the excess of amine was stripped off, leaving 44 grams or 95% of the theoretical of 3- (2,4,5 trimethylbenzylidene) ldimethylaminopropylamine as a liquid.

EXAMPLE 9 In the same apparatus, 15 grams or 0.1 mol of 2,4,5-trimethylbenzaldehyde and 3 grams or 0.05 mol of ethylene diamine were reacted in benzene, distilling out 0.1 mol of water. The product, bis (2,4,5 benzilidene)-ethylene diamine was recovered as leafy white crystals melting at 1 l0l 15 C.

EXAMPLE 10 Other substituted benzaldehydes were similarly reacted as in Examples 8 and 9; for example, 6-nitro piperonal (otherwise, 2-nitro-4, 5-methylenedioxybenzaldehyde) yielded, with ethylene diamine, (2-nitro-4,

5-methylenedioxybenzylidene)-ethylene diamine.

EXAMPLE 1 1 In the same manner, 6-nitropiperonal yielded 3-(2- nitro-4, S-methylenedioxybenzylidene) ldimethylaminopropylamine.

EXAMPLE 12 In the same manner as in Example 9, the nitro substituted piperonal was reacted with one half a molar equivalent of ethylene diamine to yield the corresponding bis-(-2-nitro)- 4, S-benzylidene) diamine.

EXAMPLE 13 The Schiff bases of the preceding examples may be reduced, if it is so desired, to the correspondingbenzylamino derivatives; for example, by treatment with sodium borohydride in methanol, or by hydrogenation in the presence of Raney nickel.

EXAMPLE 14 pension of a 24 hour culture of the test bacteria or fungi, to give a final bacterial count of l to 10 million organisms per ml; or a fungi count of from 10,000 to 50,000 spores per ml; or 30,000 cells per ml. for algae.

lowest concentration of test material not permitting macroscopic growth is designated as the Minimum lnhibitory Level. The test organisms employed were: Ethylene diamine=ED; Diethylene triamine==DT; Hy- Escherichia colo E.C.; Pseudomonas aeruginosa droxyethyl ethylene diamine=HEED; Dimethylamino- Ps. a.; Staphylococcus aureus S.a.; Streptococcus propylamine DMAPA. faecalis S.p.; Aspergillus niger An; Penicilium ex- The inVentiOn a m d S pansum P.e.; and Chlorella pyranoidosa C.p.. 5 l. A method of inhibiting bacteria and fungi which In the following Table, for the sake of brevity, the decomprises applying to said bacteria and fungi an effecrivatives of the given amines will be given as: tive amount sufficient to inhibit the growth of said bac- Trimethylbenzyl TMB; Trimethylphenyl TMP; teria and fungi of trimethylbenzylaminoethylamine.

Table 1 Parts per million of product inhibiting:

Gram Ngga tive Gram Positive Fungus Algae Product Etc. Ps.:i. S.a. Sf. A.n. IP.e. Cp. TMB/ED 50 I I00 50 O 50 I0 TMB/DT 50 500 50 50 500 500 50 TMB/HEED 500 I000 50 50 500 500 50 TMB/DMAPA 500 I000 50 I00 I00 I00 I0 TMB/DMAPA 500 I000 50 I00 I00 I00 I0 TMB/ED I00 I000 I00 500 500 I000 50 Bis TMB/ED 100 I000 I00 I00 I00 500 50 Bis TMB/DMAPA I00 500 10 I0 I00 500 I0 I TCB/DT I00 I00 50 50 I000 IO00 TCB/HEED 500 IO0O l000 I000 1000 I00O TCB/ED I00 250 I00 I00 

